scholarly journals Impact of Donor Age and Relationship on Outcomes of Peripheral Blood Haploidentical Hematopoietic Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2924-2924
Author(s):  
Aaron Pruitt ◽  
Feng Gao ◽  
Elisa De Togni ◽  
Aaron Singareddy ◽  
Hunter Cochran ◽  
...  
Keyword(s):  
Overall Survival ◽  
Peripheral Blood ◽  
Hematopoietic Cell Transplantation ◽  
Univariate Analysis ◽  
Donor Age ◽  
Relapse Risk ◽  
Hla Dr ◽  
Haploidentical Hematopoietic Cell Transplantation ◽  
Donor Characteristics ◽  
Cmv Status

Abstract Introduction: Haploidentical hematopoietic cell transplantation (haplo-HCT) is an increasingly utilized therapy for a variety of hematologic malignancies. Determining which donor characteristics affect transplant outcomes is of particular interest in haplo-HCT, as there are often multiple donors available for a given patient. A survival benefit with younger donors has been reported in some recent observational studies (DeZern et. al., Blood Advances, March 2021); (Canaani et. al., AJH, Sep. 2017). A decrease in non-relapse mortality (NRM) and increase in relapse with no overall survival difference associated with younger donors has also been observed (Mariotti et. al., Blood Advances, June 2020). These previous studies have utilized populations with bone marrow as the predominant stem cell source. Solomon et al. (BBMT Sep. 2018) observed poorer survival, increased relapse, and worse NRM with parent donors relative to children in a largely peripheral blood population. HLA DR and DP mismatch were noted to be associated with improved survival. Here we describe outcomes in peripheral blood haplo-HCT and their association with potentially selectable donor characteristics including age and relationship to the patient. Patients and Methods: We performed a retrospective review of patients who underwent peripheral blood haplo-HCT with PtCy from July 2009 through May 2021. A total of 323 patients were identified with AML (205), ALL (43), MDS (26), and other (49). Univariate and multivariate analyses (MVA) were conducted examining the effect of donor characteristics on overall survival (OS), NRM, relapse, acute and chronic GVHD. Donor characteristics included age, relationship, ABO status, CMV status, and HLA match grade. We controlled for patient characteristics known to affect outcomes including disease type, DRI, HCT CI, KPS, active disease at transplant, myeloablative conditioning, and prior HCT. Results: Median donor age was 40 (range 15-71) with male predominance (64%). Most were ABO compatible (63%) - 12% had major ABO mismatch, 20% minor, and 4% bidirectional. Donor-recipient CMV status matched in 61% of pairs, 13% were donor positive-recipient negative, 26% donor negative-recipient positive. Most were 5/10 HLA matched (51%) with 20% 6/10 and 13% 7-9/10. Univariate analysis revealed that increasing donor age was associated with higher NRM (HR 2.29, p=0.005 for donors age 30-44; HR 2.06, p=0.012 age > 44) but lower relapse risk (HR 0.56, p=0.012 age 30-44; HR 0.69, p=0.10 age > 44). There were no differences in aGVHD or cGVHD based on donor characteristics in univariate analysis. In MVA, relapse risk was lower in patients with older donors , p=0.046). In contrast, NRM was higher in patients with older donors (HR 1.73 age 30-44, HR 1.69 age > 44, p=0.010). There was no difference in overall survival based on donor age (HR 1.23 age 30-44, HR 1.38 age > 44, p=0.11). We next examined the effect of donor relationship on outcomes while controlling for donor age, patient age, and patient disease risk factors. We found no difference in outcomes between parent, sibling, or child donors. Conclusions: Increasing donor age was associated with lower relapse risk but higher NRM. These competing effects resulted in no difference in OS based on donor age. Other donor factors including relationship (parent / sibling / child), CMV status, ABO mismatch, donor sex, and HLA match grade were not associated with outcomes. Solomon et al. reported better outcomes with child compared to parent donors, a finding not replicated here, however our analysis controlled for donor age which could have been a proxy for relationship in their study. These data suggest that in peripheral blood haplo-HCT, younger donors may be preferred in patients with high risk of transplant related complications. In contrast, older donors may be preferred in patients where relapse risk is high. Data on HLA-DR and DP match is being analyzed and will be presented at the ASH 2021 meeting. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Pre-Treatment WT1 mRNA Expression Level In Peripheral Blood Predicts Response and Overall Survival Of Myelodysplastic Syndrome Patients In The Azacitidine Era

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1528-1528
Author(s):  
Tomoyasu Jo ◽  
Kazuya Sakai ◽  
Hiroyuki Muranushi ◽  
Yusuke Okamoto ◽  
Taku Tsukamoto ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Mrna Expression ◽  
Peripheral Blood ◽  
Univariate Analysis ◽  
Pre Treatment ◽  
Univariate Analyses ◽  
Lower Group

Abstract Background The Wilms' tumor gene (WT1), originally discovered as a tumor suppressor has been proven to have an oncogenic role in leukemia and several other cancers. WT1 mRNA expression levels in peripheral blood (PBWT1) has been reported as a useful marker for the risk evaluation of myelodysplastic syndrome (MDS). In the era of hypomethylating agents, the significance of PBWT1 on MDS prognosis is still unknown. This study aimed to clarify the impact of pre-treatment PBWT1 levels on overall response (OR) and overall survival (OS) in MDS patients treated with azacitidine (AZA). Patients and Methods We retrospectively analyzed all patients from March 2011 to March 2013 with World Health Organization 2008 defined MDS, CMML or AML with 20–30% bone marrow blasts who received AZA treatment in our department for at least one cycle (37.5–75.0 mg/m2/day during 7 days, every 28 days). Patients' peripheral blood specimens were collected before AZA initiation, mRNA was extracted from leukocytes using the RNeasy Mini-Kit (Qiagen, Valencia, CA), and the amount containing WT1 mRNA was measured using a WT1 mRNA Assay Kit (Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan). Hematologic response was evaluated according to International Working Group 2006. OR was defined as a best overall response of complete remission (CR), partial remission, marrow CR, or hematologic improvement. Univariate analyses for OR were carried out using Fisher's exact test. Factors associated with at least borderline significance (p < 0.10) were subjected to a multivariate analysis, using logistic regression model. OS was estimated according to the Kaplan-Meier method. Multivariate analysis was performed with proportional hazard Cox model, including all variables with p < 0.10 in univariate analyses. Results Of 55 patients enrolled, pre-treatment PBWT1 levels were available in 41 patients and the median level was 790 copies/µg RNA (range, less than 50–310000). Baseline characteristics according to PBWT1 levels (≤ 790 [lower group] [n = 21] and > 790 [higher group] [n = 20]) are summarized in Table 1. Median number of AZA treatment cycles was 4 (range, 1–18). Four patients (2 in higher group, and 2 in lower group) received allogeneic stem cell transplantation (alloSCT) after AZA treatment. OR rates were significantly lower in PBWT1 higher group than lower group (30.0 vs 71.4%, p = 0.03). In univariate analysis, other significant risk factors or with borderline significance for OR were higher serum ferritin levels (> 1000 ng/ml) and RBC transfusion dependency ≥ 4 units/8 weeks. In multivariate analysis, higher PBWT1 levels independently predicted reduced likelihood of OR (odds ratio = 0.212, 95% CI 0.01-0.95, p = 0.02). OS was significantly inferior in PBWT1 higher group as shown in Figure 1. In univariate analysis, other significant factor was Revised International Prognostic Scoring System (IPSS-R) risk groups (high risk defined as IPSS-R high or higher, and low risk defined as IPSS-R intermediate or lower). In multivariate analysis, higher PBWT1 levels (hazard ratio [HR] = 9.75, 95% CI 1.22-77.58, p = 0.03) and IPSS-R high risk (HR=7.04, 95% CI 1.43-34.48, p = 0.02) were independent predictors for OS. Conclusion Our results suggest that PBWT1 can predict both response and survival of MDS patients treated with AZA. Although salvage therapy including alloSCT can affect the survival, poor survival might result from inferior response rates in PBWT1 high patients. In MDS with high PBWT1, restoration of epigenetically silenced tumor suppressor genes with AZA might not induce apoptosis. We propose that alternative therapeutic strategies should be sought in MDS patients with high PBWT1 levels. Disclosures: No relevant conflicts of interest to declare.

Donor KIR B Haplotype Is Associated with a Increased Rate of Leukemia Relapse and Worse Overall Survival after HLA Match Sibling Pediatric Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5926-5926
Author(s):  
Antonio Pérez-Martínez ◽  
Isabel Martinez ◽  
Jaime Valentin ◽  
Lucia Fernandez ◽  
Vicario José Luis ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cell ◽  
Nk Cell ◽  
Univariate Analysis ◽  
Blood Stem Cell ◽  
Leukemia Relapse

Abstract Introduction Graft versus leukemia (GvL) effect after hemotopoietic stem cell transplantation (HSCT) is mediated by donor immune cells recovery. Natural Killer (NK) cell alloreactivity is controlled by the interaction of activatory receptors and inhibitory killer-immunoglobulin-like receptors (KIRs) with major histocompatibility locus class I antigens on the leukemia cells. Haploidentical setting is a plattform for NK cell alloreactivity however HLA identical setting remains unclear. Methods and Patients We performed KIR-genotyping of HLA-identical sibling donors in 35 pediatric CD34 selection peripheral blood stem cell transplantations to identify genetic factors affecting leukemia relapse and overall survival. Univariate analysis of leukemia relapse and KIR genotyping was performed in order to identify independent variables predictive of outocome for pediatric acute lymphoblastic leukemia (ALL), (n=20) and acute myeloblastic leukemia (AML), (n=15). Results Donor B haplotype was observed in 21 cases (60%). Statistical analysis shown that donor B haplotype was associated with significantly more relapse in leukemia pediatric patients (38% vs. 0%) and worse overall survival (40% vs. 7%). Further analysis revealed that 2DL5a, 2DS3 and 2DS5 were associated with an increased rate of leukemia relapse (47% vs. 6%, 54% vs. 10% and 58% vs. 13%, respectively) and 2DL5a, 2DS1 and 3DS1 were associated with a worse overall survival (48% vs. 6%, 64% vs. 10% and 58% vs. 13%, respectively). No difference was observed in patients KIR haplotype or donor-recipient KIR haplotype mismatch. Conclusion In our study, which included only reduced intensity conditioning without antithymocyte globulin followed by related peripheral blood stem cell transplantation, we found a significant worse impact of donor KIR B haplotype in stem cell transplantation outcome. Our results suggest that donor KIR B haplotype (2DL5a, 2DS3 and 2DS5) increases leukemia relapse and also donor KIR B haplotype (2DL5a, 2DS1 and 3DS1) confer significant survival damage to HLA-identical sibling HSCT. Figure 1. Donor KIR genotyping (2DL5A, 2DS1 and 3DS1) impacts in overall survival. Figure 1. Donor KIR genotyping (2DL5A, 2DS1 and 3DS1) impacts in overall survival. Disclosures No relevant conflicts of interest to declare.

scholarly journals Selecting the Best Donor for T Cell-Replete Haploidentical Transplantation: Importance of HLA Disparity, NK Alloreactivity, and Other Clinical Variables

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 670-670
Author(s):  
Scott R Solomon ◽  
Michael A Aubrey ◽  
Xu Zhang ◽  
Allison Piluso ◽  
Brian M Freed ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Risk Index ◽  
Donor Selection ◽  
Unrelated Donor ◽  
Receptor Ligand ◽  
Clinical Variables ◽  
Hla Dr ◽  
Cox Analysis ◽  
Donor Characteristics

Abstract Lack of a matched sibling or unrelated donor can be a significant barrier to allogeneic hematopoietic cell transplantation (HCT). Haploidentical (haplo) donors are readily available for nearly all such patients. However, donor selection criteria to determine the optimal haplo donor are not readily available. In order to determine which donor characteristics are most important in predicting transplant success, we retrospectively analyzed 208 consecutive donor-recipient pairs receiving haplo HCT with post-transplant cyclophosphamide for hematologic malignancy. Donor characteristics were evaluated by multivariate Cox analysis and correlated with overall survival (OS), disease-free survival (DFS), relapse/progression, and non-relapse mortality (NRM), while controlling for significant patient and transplant-related factors. Donor variables analyzed included age, sex, relationship to recipient, CMV status, ABO compatibility, HLA disparity and several NK alloreactivity models (KIR receptor-ligand, ligand-ligand, haplotype, B content, activating KIR-based education systems, Sekine donor licensing model). Median (range) recipient and donor age was 52 (19-75) and 38 (15-73) years respectively, and 41% of donor-recipient pairs were non-Caucasian. Patients were transplanted for AML (34%), MDS/MPS/CML (20%), ALL (17%), NHL/HD/CLL (25%). PBSC was used as the stem cell source in 66% of patients, and conditioning intensity was myeloablative in 41%. The donor was a child, sibling, or parent in 47%, 38%, and 14% respectively. Median (range) follow-up for surviving patients was 33 (7-130) months. In multivariate Cox analysis, patient/transplant characteristics associated with improved OS and DFS included recipient age &lt;55 years, black race, CMV seronegativity, low/intermediate disease risk index (DRI), and more recent transplant year. When adjusting for significant patient/transplant variables, donor characteristics independently associated with improved overall survival included presence of HLA-DR mismatch [GVH direction] (HR 0.35, p=0.010), the presence of HLA DP non-permissive mismatch [GVH direction] (HR 0.51, p=0.033), KIR receptor-ligand mismatch (HR 0.56, p=0.023), the presence of KIR B/x haplotype with KIR2DS2 (HR 0.38, p=0.005 vs. B/x without KIR2DS2; HR 0.47, p=0.013 vs. A/A), donor CMV positivity (HR 0.49, p=0.009) and donor relation (child vs. parent - HR 0.31, p=0.016; sibling vs. parent - HR 0.48, p=0.087). Donor characteristics independently associated with reduced risk of disease relapse/progression included the presence of KIR receptor-ligand mismatch (HR 0.39, p=0.001), KIR B/x haplotype with KIR2DS2 (HR 0.43, p=0.023 vs. B/x without KIR2DS2), the presence of ≥4 (out of 10) HLA allelic mismatches [GVH direction] (HR 0.29, p=0.001), the presence of a non-permissive HLA-DP mismatch (HR 0.25, p&lt;0.001) and the use of a non-parental donor (child vs. parent - HR 0.26, p=0.010; sibling vs. parent - HR 0.37, p=0.039). Donor characteristics associated with increased NRM included higher HLA disparity (HR 7.86, p=0.016), HLA-DR match (HR 15.99, p&lt;0.001), absence of KIR B/x haplotype with KIR2DS2 (A/A haplotype - HR 5.03, p=0.003; B/x without KIR2DS2 - HR 3.92, p=0.034), CMV seronegativity (HR 2.99, p=0.026), and female donor-male recipient (HR 2.35, p=0.071). Adjusted 3-yr OS was improved in patients with the presence of KIR R-L mm (66% vs 50%, p=0.013), KIR B/x with KIR2DS2 (69% vs. 55% [A/A] or 43% [B/x without KIR2DS2, p=0.052 and 0.007, respectively]), HLA-DR mm (64% vs. 45%, p=0.071), and HLA-DP non-permissive mm (72% vs. 56%, p=0.026), emphasizing the importance of donor HLA and KIR typing for optimal donor selection (see figure). This large, single institution analysis demonstrates the significance of HLA-DR/HLA-DP disparity, NK alloreactivity, and other clinical variables in the donor selection process for haplo HCT. These results suggest that HLA-DP and donor KIR typing should be performed routinely in T cell-replete haplo HCT to assist in donor selection and risk stratification. Disclosures Solh: ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau.

scholarly journals Baseline Body Mass Index Among Children and Adults Undergoing Allogeneic Hematopoietic Cell Transplantation: Clinical Characteristics and Outcomes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2558-2558
Author(s):  
Michael Gleimer ◽  
Yumeng Li ◽  
Lawrence Chang ◽  
Sophie Paczesny ◽  
David Hanauer ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Bone Marrow ◽  
Overall Survival ◽  
Peripheral Blood ◽  
Cumulative Incidence ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Normal Weight ◽  
P Value ◽  
Obese Patients

Abstract Obesity is a serious public health problem accompanying changes in diet and physical activity. The rising prevalence of obesity may influence the outcomes of hematopoietic cell transplantation (HCT). We studied 898 children and adults receiving first-time allogeneic bone marrow or peripheral blood stem cell transplants between 2004 and 2012 at the University of Michigan. Pre-transplant body mass index (BMI) was calculated using height and weight measurements and treated as a continuous variable. Recipients were then classified as underweight, normal weight, overweight, or obese according to BMI for adults using the World Health Organization classification system, or age-adjusted BMI percentiles for children based on Center for Disease Control and Prevention charts. The study population was predominantly Caucasian, and the median age was 51 years (5 months – 73 years). The cumulative 3-year incidence of non-relapse mortality (NRM) in underweight, normal weight, overweight, and obese patients was 20%, 19%, 20%, and 33% (p=0.04) (Figure 1A). Major causes of NRM were acute and chronic graft-versus-host disease (GVHD) (Figure 1B). The corresponding incidence of relapse was 30%, 41%, 37%, and 30% (p=0.002) (Figure 1C). Three-year overall survival was 59%, 48%, 47%, and 43% (p=0.55) (Figure 1D). Multivariate analysis showed that obesity was associated with higher NRM (hazard ratio [HR] 1.43, p=0.04), and lower relapse (HR 0.65, p=0.002) (Table 1). Pre-transplant plasma levels of ST2 and TNFR1 biomarkers were significantly higher in obese than in normal weight patients (p=0.04 and p=0.05, respectively) (Table 2). The increase in NRM observed in obese patients was partially offset by lower incidence of relapse, resulting in no significant difference in overall survival. Figure 1. Transplant outcomes according to BMI categories. Cumulative incidence of NRM (A), chronic GVHD (B), relapse (C), and probability of overall survival (D) according to BMI groups. N = 20 underweight (UW), 290 normal weight (NW), 287 overweight (OW), 301 obese (OB). Figure 1. Transplant outcomes according to BMI categories. Cumulative incidence of NRM (A), chronic GVHD (B), relapse (C), and probability of overall survival (D) according to BMI groups. N = 20 underweight (UW), 290 normal weight (NW), 287 overweight (OW), 301 obese (OB). Table 1. Results of multivariate regression analysis by BMI category. NRM Acute GVHD Chronic GVHD Relapse Overall survival Hazard ratio (95% confidence intervals), p value Normal weight 1.00 1.00 1.00 1.00 1.00 Underweight 1.74 (0.76−4.01), 0.19 1.11 (0.56−2.21), 0.76 0.99 (0.46−2.12), 0.98 0.70 (0.32−1.50), 0.36 1.02 (0.54−1.95), 0.95 Overweight 0.95 (0.65−1.37), 0.77 1.03 (0.78−1.35), 0.85 1.07 (0.83−1.38), 0.60 0.79 (0.61−1.03), 0.08 0.85 (0.68−1.07), 0.17 Obese 1.43 (1.02−2.01), 0.04 1.15 (0.89−1.50), 0.29 1.21 (0.94−1.55), 0.14 0.65 (0.49−0.86), 0.002 0.93 (0.75−1.16), 0.55 Other covariates Continuous age 1.01 (1.00−1.02), 0.18 1.00 (0.99−1.00), 0.37 1.00 (0.99−1.01), 0.69 1.00 (1.00−1.01), 0.36 1.01 (1.00−1.02), 0.003 Malignancy Non−malignant 1.00 1.00 1.00 1.00 1.00 Malignant 0.37 (0.10−1.33), 0.13 1.73 (0.82−3.68), 0.15 1.29 (0.72−2.31), 0.38 26.50 (3.49−201.02), 0.002 2.05 (0.92, 4.58), 0.08 Relatedness Related 1.00 1.00 1.00 1.00 1.00 Unrelated 2.20 (1.65−2.94), <0.001 1.88 (1.50−2.35), <0.001 1.13 (0.92−1.39), 0.23 0.61 (0.48−0.77), <0.001 1.24 (1.03−1.49), 0.02 Transplant type Peripheral blood 1.00 1.00 1.00 1.00 1.00 Bone marrow 0.23 (0.09−0.58), 0.002 0.66 (0.44−0.99), 0.04 0.91 (0.61−1.36), 0.65 1.09 (0.72−1.66), 0.68 0.56 (0.38−0.82), 0.003 HLA match Matched 1.00 1.00 1.00 1.00 1.00 Mismatched 1.59 (1.16−2.22), 0.004 1.69 (1.30−2.17), <0.001 0.95 (0.73−1.25), 0.73 0.83 (0.60−1.18), 0.29 1.41 (1.12−1.79), 0.003 Conditioning Myeloablative 1.00 1.00 1.00 1.00 1.00 Reduced 1.02 (0.76−1.35), 0.91 1.19 (0.94−1.49), 0.14 1.02 (0.82−1.27), 0.82 0.90 (0.69−1.16), 0.42 0.89 (0.74−1.09), 0.24 Year of transplant 2004−2008 1.00 1.00 1.00 1.00 1.00 2009−2013 0.79 (0.60−1.05), 0.10 0.76 (0.61−0.95), 0.02 0.96 (0.79−1.17), 0.70 0.76 (0.60−0.95), 0.02 0.78 (0.65−0.94), 0.01 Table 2. Baseline levels of plasma biomarkers suppression of tumorigenicity 2 (ST2) and tumor necrosis factor receptor 1 (TNFR1) by BMI category. ST2 TNFR1 BMI category N Median concentration (IQR), pg/ml p value N Median concentration (IQR), pg/ml p value Normal weight 115 131 (0-628) − 88 2129 (1486-3232) − Underweight 7 256 (82-659) 0.51 7 1596 (1467-2971) 0.57 Overweight 115 208 (0-845) 0.22 81 2266 (1708-3725) 0.32 Obese 110 257 (0-1045) 0.04 99 2644 (1922-3395) 0.05 Disclosures No relevant conflicts of interest to declare.

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